Wnt signaling pathways are a network of proteins in eukaryotic cells that are important for regulating cell growth and differentiation. Logan C Y and Nusse R, “The Wnt signaling pathway in development and disease.” Annu. Rev. Cell. Dev. Biol. 20:781-810 (2004); Nusse R., “Wnt signaling in disease and in development.” Cell Res. 15(1):28-32 (January 2005); Clevers H, “Wnt/beta-catenin signaling in development and disease.” Cell 127(3):469-80 (3 Nov. 2006). Wnt signaling is essential for regulating cell growth and differentiation during embryonic development. In adults, Wnt signaling promotes tissue homeostasis.
Dysregulation of Wnt signaling has been implicated in many human diseases. Aberrant over-activation of Wnt pathway can be involved in causing tumorigenesis of colorectal carcinomas. Conversely, pathologically low levels of Wnt signaling have been associated with osteoporosis, osteoarthritis, polycystic kidney disease and neurodegenerative diseases. Controlled activation of Wnt pathway has been shown to promote regenerative processes such as tissue repair and wound-healing. Zhao J, Kim K A and Abo A, “Tipping the balance: modulating the Wnt pathway for tissue repair.” Trends Biotechnol. 27(3):131-6 (March 2009).
Wnt proteins are proteins ligands that bind to cell surface receptors (the “Wnt receptor complex”) to activate Wnt pathways in a cell. Several kinds of Wnt pathways have been identified, both canonical and non-canonical.
Wnt signaling through a canonical Wnt/β-catenin pathway regulates the cellular turn-over of the transcription cofactor protein β-catenin. MacDonald B T, Tamai K and He X, “Wnt/beta-catenin signaling: components, mechanisms, and diseases.” Dev. Cell 17(1):9-26 (July 2009) and U.S. Patent Application 2009/0220488, entitled “Evaluating and treating scleroderma”. In the absence of Wnt ligands, β-catenin remains phosphorylated by a multi-protein “destruction complex”, which triggers polyubiquitination of the β-catenin and degradation of β-catenin in the proteosomes of the cell. When Wnt binds to the Wnt receptor complex, β-catenin is stabilized through inhibition of the “destruction complex”. The β-catenin then translocates to the nucleus. In the nucleus, β-catenin activates transcription of Wnt target genes and thus activates the gene expression programs for cell growth and differentiation.
In the canonical Wnt/β-catenin pathway, Frizzled (FZD) proteins and Low-Density-Lipoprotein Receptor-Related Protein 5/6 (LRP5/6) form the receptor complex. Both Frizzled proteins and LRP5/6 are important for the canonical Wnt/β-catenin pathway.
In a non-canonical, β-catenin independent pathway, Wnt signaling regulates planar cell polarity (PCP) or tissue polarity signaling, which governs cells and tissue movements. Zallen J A, “Planar polarity and tissue morphogenesis.” Cell 129(6):1051-63 (15 Jun. 2007); Simons M and Mlodzik M, “Planar cell polarity signaling: from fly development to human disease.” Annu. Rev. Genet; 42:517-40 (2008); U.S. Patent Application 2009/0220488. Frizzled proteins are receptors in the non-canonical Wnt signaling, but LRP5/6 is not essential.
Despite the many proteins that are involved in Wnt signaling pathways, few druggable targets in the pathway have been identified, especially targets upstream in the pathway of β-catenin in the Wnt pathway. A need exists for agents that potentiate Wnt signaling, to develop therapies for Wnt signaling-related disorders.